Ubiquinol and alpha lipoic acid compositions

ABSTRACT

The present invention is directed to compositions and methods of delivery of CoQ that is reduced in the presence of lipoic acid and, optionally a fatty acid and/or optionally in a monoterpene. The compositions that include the reduced CoQ can be formulated in soft gel capsules.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a division of U.S. patent application Ser. No.12/048,350, now U.S. Pat. No. 8,343,541 filed Mar. 14, 2008, entitled“Ubiquinol and Alpha Lipoic Acid Compositions,” which claims benefitunder 35 U.S.C. §119(e) to U.S. Serial Nos. 60/895,057, entitled“CoEnzyme Q-10 and Fatty Acid Compositions”, filed Mar. 15, 2007 byMichael Fantuzzi, 60/908,477, entitled “Ubiquinol and Alpha Lipoic AcidCompositions”, filed Mar. 28, 2007 by Michael Fantuzzi and 60/977,234,entitled “Ubiquinol and Alpha Lipoic Acid Compositions”, filed Oct. 3,2007 by Michael Fantuzzi, the contents of which are incorporated hereinby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the solubilization of coenzyme Q-10 andanalogs thereof, at least one fatty acid and alpha lipoic acid, therebyproviding coenzyme Q-10 in reduced form (ubiquinol).

BACKGROUND OF THE INVENTION

CoQ-10 (coenzyme Q-10) is a fat-soluble quinone that is structurallysimilar to vitamin K and commonly known as ubiquinone. CoQ-10 is foundin most living organisms, and is essential for the production ofcellular energy. CoQ-10 (2,3 dimethyl-5 methyl-6-decaprenylbenzoquinone) is an endogenous antioxidant found in small amounts inmeats and seafood. Although CoQ-10 is found in all human cells, thehighest concentrations of CoQ-10 occur in the heart, liver, kidneys, andpancreas. It is found naturally in the organs of many mammalian species.

CoQ-10 can be synthesized in the body or it can be derived from dietarysources. Situations may arise, however, when the need for CoQ-10surpasses the body's ability to synthesize it. CoQ-10 can be absorbed byoral supplementation as evidenced by significant increases in serumCoQ-10 levels after supplementation.

CoQ-10 is an important nutrient because it lies within the membrane of acell organelle called the mitochondria. Mitochondria are known as the“power house” of the cell because of their ability to produce cellularenergy, or ATP, by shuttling protons derived from nutrient breakdownthrough the process of aerobic (oxygen) metabolism. CoQ-10 also has asecondary role as an antioxidant. CoQ-10, due to the involvement in ATPsynthesis, affects the function of almost all cells in the body, makingit essential for the health of all human tissues and organs. CoQ-10particularly effects the cells that are the most metabolically active:heart, immune system, gingiva, and gastric mucosa

Several clinical trials have shown CoQ-10 to be effective in supportingblood pressure and cholesterol levels. Furthermore, CoQ-10 has also beenshown to improve cardiovascular health. CoQ-10 has been implicated asbeing an essential component in thwarting various diseases such ascertain types of cancers. These facts lead many to believe that CoQ-10supplementation is vital to an individual's well being.

CoQ-10 is sparingly soluble in most hydrophilic solvents such as water.Therefore, CoQ-10 is often administered in a powdered form, as in atablet or as a suspension. However, delivery of CoQ-10 by these methodslimits the bioavailability of the material to the individual.

Reduced benzoquinones in general, including reduced CoQ-10, areeffective reducing agents for oxygen or lipid radicals. Reduced CoQ-10appears to function as part of a complex chain of antioxidant activity.CoQ-10 helps facilitated reduction of radicals of alpha-tocopherol andascorbate formed when these antioxidants are oxidized by oxygen orcarboxyl radicals. There are no known enzymes for direct reduction ofthe tocopheryl radical or external ascorbate radical, but there areenzymes in all membranes which can reduce CoQ-10 and the reduced CoQ-10can reduce the tocopheryl or ascorbate radicals to restore tocopherol orascorbate.

CoQ-10 in endo membranes or plasma membranes is extensively in thereduced form, most of the CoQ-10 in total rat and human tissue is in thereduced form and most of the CoQ-10 in serum is in the reduced state.

There is a need in the art for an improved methodology to deliverincreased amounts of bioavailable CoQ-10 to an individual in needthereof.

BRIEF SUMMARY OF THE INVENTION

The present invention pertains to the surprising discovery thatubiquinone (CoQ-10) is reduced in the presence of lipoic acid,optionally, in combination with one or more fatty acid(s) and,optionally, in combination with a monoterpene such as limonene.Furthermore, the reduced form of CoQ-10 (ubiquinol) is stable in thepresence of alpha lipoic acid, optionally, with one or more fatty acidsand, optionally, in combination with a monoterpene such as limonene.

In one aspect, the present invention provides compositions of ubiquinolin combination with a fatty acid. In another aspect, the presentinvention provides ubiquinol in combination with alpha lipoic acid in asufficient amount such that the ubiquinol remains in the reduced form(ubiquinol) and does not significantly oxidize to ubiquinone. In yetanother aspect, the present invention provides ubiquinol in combinationwith alpha lipoic acid in a sufficient amount such that the ubiquinolremains in the reduced form (ubiquinol) and does not oxidize toubiquinone in combination with one or more fatty acids. In still anotheraspect, the present invention provides ubiquinol in combination withalpha lipoic acid in a sufficient amount such that the ubiquinol remainsin the reduced form (ubiquinol) and does not oxidize to ubiquinone incombination with a monoterpene, such as limonene. In another aspect, thepresent invention provides ubiquinol in combination with alpha lipoicacid in a sufficient amount such that the ubiquinol remains in thereduced form (ubiquinol) and does not oxidize to ubiquinone incombination with a monoterpene, such as limonene, and one or more fattyacid(s).

The compositions of the invention are useful as dietary supplements oras nutraceuticals.

In particular, the compositions of the invention noted throughout theapplication are included in a soft gelatin (soft gel) capsule.Typically, the soft gelatin capsule encapsulates at least 5% by weightof the reduced CoQ-10 (from the combination of alpha lipoic acid,optionally a fatty acid(s) and CoQ-10, or ubiquinol in the presence ofalpha lipoic acid, optionally in combination with a fatty acid) that canoptionally be solubilized in at least one monoterpene. Typicalmonoterpenes include, for example, limonene, perillyl alcohol, perillicacid, cis-dihydroperillic acid, trans-dihydroperillic acid, methylesters of perillic acid, methyl esters of dihydroperillic acid,limonene-2-diol, uroterpenol, and combinations thereof.

In another embodiment, the present invention pertains to methods fordelivery of an effective amount of bioavailable reduced CoQ-10 and/orCoQ-10, to an individual. The method includes providing reduced CoQ-10and/or CoQ-10 provided by the compositions of present invention, suchthat an effective amount of reduced CoQ-10 and/or CoQ-10 is provided tothe individual.

In still another embodiment, the present invention also includespackaged formulations of the invention and instructions for use of thetablet, capsule, elixir, etc.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the invention. As will be realized, theinvention is capable of modifications in various obvious aspects, allwithout departing from the spirit and scope of the present invention.Accordingly, the drawings and detailed description are to be regarded asillustrative in nature and not restrictive.

DETAILED DESCRIPTION

The present invention pertains to the surprising discovery thatubiquinone (CoQ-10) is reduced to reduced CoQ-10 (ubiquinol) in thepresence of lipoic acid (e.g., alpha lipoic acid). Ideally, there is atleast a molar equivalent of each of alpha lipoic acid and CoQ-10, sothat the CoQ-10 is reduced to at least 95% or greater, e.g., 99 to 100%.In particular, a molar excess of alpha lipoic acid is used to helpreduce the CoQ-10 to essentially only ubiquinol. In one aspect, one ormore fatty acid(s) are included in the compositions. In another aspect,a monoterpene, such as limonene, is included with either theCoQ-10/alpha lipoic acid combination, optionally with one or more fattyacids, or ubiquinol is simply dissolved in the monoterpene, such aslimonene, with or without a fatty acid and in the presence of alphalipoic acid.

In another embodiment, the compositions include ubiquinol that isalready reduced and is maintained with a sufficient quantity of alphalipoic acid to help prevent oxidation of the ubiquinol back to theoxidized form of the ubiquinone. Again, the composition can include,optionally, either one or more fatty acid(s), a monoterpene such aslimonene, or both.

The term “coenzyme Q” or “ubiquinone” is used throughout the presentspecification to describe a group of lipid soluble benzoquinonesinvolved in electron transport in mitochondrial preparations, i.e., inthe oxidation of succinate or reduced nicotine adenine dinucleotide(NADH) via the cytochrome system. The compounds can be described as:coenzyme Q_(n) where n is 1 through 12 or ubiquinone (x) in which xdesignates the total number of carbon atoms in the side chain and can beany multiple of 5. Differences in properties are due to the differencein the chain length.

In one embodiment of the invention, the reduced form of coenzyme Q-10 istermed “ubiquinol”. It should be understood that throughout the presentspecification that reference to coenzyme Q-10, CoQ-10, CoQ andubiquinone all refer to this group of benzoquinones (where n is 1through 12) and the terms are used interchangeably.

The term “ubiquinol” is used throughout the specification to describethe reduced form of coenzyme Q which is used as the active ubiquinone incompositions according to the present invention. In ubiquinol, thequinone ring of coenzyme Q is reduced such that the structure of thecompound appears as set forth below. In ubiquinol, n in one embodimentis 10 and is derived from coenzyme Q-10. The amount of ubiquinol whichis included in compositions according to the present invention rangesfrom about 0.1% to about 50% by weight of the final composition whichcan be encapsulated in a soft gelatin capsule, more particularly about0.5% to about 10% by weight, even more particularly about 1% to about 5%by weight.

It should be understood that throughout the present specification thatreference to reduced coenzyme Q-10, reduced CoQ-10, reduced CoQ andubiquinol all refer to this group of reduced benzoquinones (where n is 1through 12) and the terms are used interchangeably.

A commercial source of ubiquinol is QH™, Kaneka Corporation, FunctionalFoods Development Division, 3-2; 1-, Nakanoshima, Kita-Ku, Osaka530-8288, Japan.

CoQ-10 is found in most living organisms, and is essential for theproduction of cellular energy. Ubiquinone is a naturally occurringhydrogen carrier in the respiratory chain (coenzyme Q) and structurally,it is a 2,3-dimethoxy-5-methyl-1,4-benzoquinone with a multiprenyl sidechain, the number of isoprene units varying depending upon the organismfrom which it is derived. CoQ-10 analogs include reduced andsemi-reduced CoQ-10 and ubiquinone derivatives described, for example,in WO 8803015, the teachings of which are incorporated herein byreference.

Semi-reduced ubiquinone, by analogy, can be depicted as a radicalspecies (CoH.):

wherein n is as described above.

In certain embodiments, the CoQ is reduced in the presence of lipoicacid and, optionally, at least one fatty acid to provide a compositionthat includes at least about 50% reduced CoQ, more particularly, atleast about 75% reduced CoQ, even more particularly, at least about 95%,97%, 99%, 99.5% reduced CoQ based on a weight basis of the originalweight of oxidized CoQ. In certain aspects, the oxidized form of CoQcannot be detected when in the presence of an effective amount of lipoicacid and, optionally, a fatty acid and, optionally, a monoterpene.Typically, an effective amount of lipoic acid is at least a molarequivalent of lipoic acid to the oxidized CoQ. In instances whereubiquinol is the sole component, then alpha lipoic acid can be used tomaintain the ubiquinol in a reduced state. Thus, the invention providesreduced CoQ compositions that are stable to oxidation.

The terms “lipoic acid” and “alpha lipoic acid” are used interchangeablyherein and both refer to 1,2-dithione-3-pentanoic acid, also known asthioctic acid.

Lipoic acid exists as two enantiomers: the R-enantiomer and theS-enantiomers. Naturally-occurring lipoic acid occurs in the R-form, butsynthetic lipoic acid (commonly known as alpha lipoic acid) is a racemicmixture of R-form and S-form. It should be understood that throughoutthe application, reference to lipoic acid therefore includes theR-enantiomer, the S-enantiomer, and the racemic mixture of R/Senantiomers.

The phrase “fatty acid,” as used herein means an organic compoundcomposed of unsubstituted alkyl or alkenyl groups containing 4 to 22carbon atoms and characterized by a terminal carboxylic acid group.

Useful fatty acids include butyric acid (butanoic acid) caproic acid(hexanoic acid), caprylic acid (octanoic acid), capric acid (decanoicacid), caproleic acid (dec-9-enoic acid), lauric acid (dodecanoic acid),lauroleic acid (cis-5-lauroleic), myristic acid (tetradecanoic acid),myristoleic acid (cis-9-tetradecenoic), palmitic acid (hexadecanoicacid), palmitoleic acid (9-hexadecenoic acid), stearic acid(octadecanoic acid), oleic acid (9-octadecenoic acid), ricinoleic acid(12-hydroxy-9-octadecenoic acid), vaccenic acid (11-octadecenoic acid),valeric acid (pentanoic acid), linoleic acid (9,12-octadecadienoicacid), alpha-linolenic acid ((ALA) 9,12,15-octadecatrienoic acid),gamma-linolenic acid ((GLA) 6,9,12-octadecatrienoic acid), arachadonicacid (eicosanoic acid), gadoleic acid (9-eicosenoic acid), arachidonicacid ((AA) 5,8,11,14-eicosatetraenoic acid), EPA(5,8,11,14,17-eicosapentaenoic acid), behenic acid (docosanoic acid),erucic acid (13-docosenoic acid), DHA (4,7,10,13,16,19-docosahexaenoic),pelargonic acid (nonanoic acid), steridonic acid(6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoic acid) and lignoceric acid(tetracosanoic acid). In one aspect, the fatty acid is considered acarrier and dissolves the ingredients within the soft gelatin capsule.Suitable ingredients include ALA and ubiquinol and/or ubiquinone.

In one aspect, the lipoic acid 25% (weight lipoic acid/weight fattyacid(s)) (i.e., alpha-lipoic acid) is first dissolved in a mixture oftwo fatty acids, capric and caprylic acids at an elevated temperature ofbetween about 25° C. and about 35° C. in, for example, a 3:7 ratio ofthe fatty acids. In one embodiment, the lipoic acid/fatty acid mixtureis then dissolved in a monoterpene, such as limonene.

The encapsulation mixtures of the invention (mixtures ofubiquinone/ubiquinol with or without a monoterpene, and/or one or morefatty acids) result in encapsulation solutions that are crystal free.This is one unique aspect of the present invention that is believed toprovide enhanced bioavailability of active agents to the individual inneed thereof.

Therefore, it is possible to prepare encapsulation solutions ofubiquinone/ALA/monoterpene, ubiquinol/ALA/monoterpene,ubiquinone/ALA/fatty acid(s), ubiquinol/ALA/fatty acid(s),ubiquinone/ALA/monoterpene/fatty(acid) orubiquinol/ALA/monoterpene/fatty acid(s) suitable for encapsulationwithin a soft gelatin capsule. In one aspect, the monoterpene islimonene. In another aspect, the encapsulation solution is free ofsolids, such as crystallization of the active agent(s), such as ALA,ubiquinol or ubiquinone.

L-carnitine is recognized in the art and facilitates transport ofmaterials through the mitochondrial membrane. L-carnitine is anessential fatty acid metabolism cofactor that helps to move fatty acidsto the mitochondria from the cytoplasm. This is an important factor asthis is where CoQ-10 uptake occurs.

In one aspect of the present invention, L-carnitine is included in softgel formulations in combination with CoQ-10. Suitable ratios ofL-carnitine and CoQ-10 are known in the art and include those describedin U.S. Pat. No. 4,599,232, issued to Sigma Tau Industrie FaramaceuticheRiunite S.p.A. on Jul. 8, 1986, the teachings of which are incorporatedherein in their entirety. In particular, combinations of limonene,CoQ-10 and L-carnitine in soft gel formulations are of importance. Thepresent invention provides the advantage of solvating large amounts(relative to that of current state of the art) of CoQ-10 in limonene ina soft gel capsule along with an additive, such as L-carnitine.

It should be understood, that throughout the specification, reference ismade to CoQ-10 or amino acids, such as carnitine, and that suchreference includes the analogs thereof.

The term “amino acid” as used herein includes, but is not limited to,glycine, the L forms of alanine, valine, leucine, isoleucine,phenylalanine, tyrosine, proline, hydroxyproline, serine, threonine,cysteine, cystine, methionine, tryptophan, aspartic acid, glutamic acid,arginine, lysine, histidine, ornithine, hydroxylysine, carnitine, andother naturally occurring amino acids and analogs thereof.

For example amino acid analogs, such as carnitine “analogs” includeacetylated products, fumarate derivatives and the like, and acceptableammonium and metal salts thereof.

The term “carnitine” is also known as3-Carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, innersalt; (3-carboxy-2-hydroxypropyl)trimethylammonium hydroxide, innersalt; gamma-amino-beta-hydroxybutyric acid trimethylbetaine;gamma-trimethyl-beta-hydroxybutyrobetaine;3-hydroxy-4-(trimethyl-ammonio)butanoate. See The Merck Index (1989), p.281 and references cited therein. Therefore, “carnitine” and “carnitineanalogs” includes, but is not limited to racemic or essentially pureL-carnitine (carnitine), or a corresponding alkanoyl-carnitine such ase.g. acetyl-carnitine or propionyl-carnitine, or a suitable salt of suchcompounds such as e.g. L-carnitine tartrate, L-carnitine fumarate,L-carnitine-magnesium-citrate, acetyl-L-carnitine tartrate,acetyl-L-carnitine-magnesium-citrate, or any mixture of the aforementioned compounds.

Carnitine and carnitine analogs also include those described in U.S.Pat. Nos. 5,362,753, 4,687,782, 5,030,458, 5,030,657, 4,343,816,5,560,928, 5,504,072, 5,391,550 and 5,240,961, the teachings of whichare incorporated herein by reference in their entirety.

The phrase “sufficient quantity” of a given material, such as amonoterpene, “suitable to solubilize” is therefore intended to mean thatthat amount of a material, such as a monoterpene or a carrier (e.g., afatty acid) that will dissolve a component under a given set ofconditions, generally, those at ambient temperature. This determinationshould be understood by one skilled in the art and can be determined bymethods known in the art, such as by solubility studies.

One of the particular advantages of utilizing the combination ofubiquinol and/or CoQ with lipoic acid, optionally in molar excess,optionally, one or more fatty acids, and optionally a monoterpene, isthe ability to prevent oxidation of the ubiquinol back to thecorresponding ubiquinone. Not to be limited by theory, it is believedthat once an individual ingests the formulation of the invention, thatthe ubiquinol is then more bioavailable to the individual than theequivalent oxidized CoQ-10, and thus is better absorbed.

In one aspect, the present invention provides a molar ratio of lipoicacid to ubiquinol in the range of from about 0.1:1 to about 2.5:1 toensure that the ubiquinol remains reduced. Suitable molar ratio rangesinclude from about 0.2:1 to about 2.3:1, from about 0.4:1 to about 1.6:1and in particular about 0.9:1 to about 1.1:1.

Use of the lipoic acid in combination with the ubiquinol and/or coenzymeQ provides that the ubiquinol remains unoxidized for at least about 30days at ambient temperature, more particularly at least about 120 daysat ambient temperature and even more particularly at least about 365days, even more particularly at least about 2 years or longer at ambienttemperature, wherein at least about 85 to about 95% of the originalamount of ubiquinol remains unoxidized. In particular, at least about85%, 86%, 87% and so forth up to about 100% (e.g., 99.9%) of ubiquinolin the sample remains unoxidized (or any remaining ubiquinone is reducedto ubiquinol) over the given time frames.

A major advantage of utilizing lipoic acid with the ubiquinol and/orubiquinone is in the processing/manufacturing stages. It has beensurprisingly found that the lipoic acid helps stabilize the ubiquinol. Astable formulation of ubiquinol is much easier to handle, store and workwith because ubiquinol by itself is very easily oxidized and as such,requires very careful precise handling. Special precautions normallyneed to be taken to make sure that no air/light, temperature changestake place during the processing and manufacturing with the material.With the present invention, the material (incorporating lipoic acid) canbe handled just like any fill material and no special handling,processing or storage of the formulations is needed. This is a hugeadvantage to the manufacturer, especially since ubiquinol is veryexpensive and degrading it even a little can be very costly.

In the specification and in the claims, the terms “including” and“comprising” are open-ended terms and should be interpreted to mean“including, but not limited to . . . . ” These terms encompass the morerestrictive terms “consisting essentially of” and “consisting of.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural reference unless thecontext clearly dictates otherwise. As well, the terms “a” (or “an”),“one or more” and “at least one” can be used interchangeably herein. Itis also to be noted that the terms “comprising”, “including”,“characterized by” and “having” can be used interchangeably.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All publications and patentsspecifically mentioned herein are incorporated by reference in theirentirety for all purposes including describing and disclosing thechemicals, instruments, statistical analyses and methodologies which arereported in the publications which might be used in connection with theinvention. All references cited in this specification are to be taken asindicative of the level of skill in the art. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

The term “monoterpene” as used herein, refers to a compound having a10-carbon skeleton with non-linear branches. A monoterpene refers to acompound with two isoprene units connected in a head-to-end manner. Theterm “monoterpene” is also intended to include “monoterpenoid”, whichrefers to a monoterpene-like substance and may be used loosely herein torefer collectively to monoterpenoid derivatives as well as monoterpenoidanalogs. Monoterpenoids can therefore include monoterpenes, alcohols,ketones, aldehydes, ethers, acids, hydrocarbons without an oxygenfunctional group, and so forth.

It is common practice to refer to certain phenolic compounds, such aseugenol, thymol and carvacrol, as monoterpenoids because their functionis essentially the same as a monoterpenoid. However, these compounds arenot technically “monoterpenoids” (or “monoterpenes”) because they arenot synthesized by the same isoprene biosynthesis pathway, but rather byproduction of phenols from tyrosine. However, common practice will befollowed herein.

Suitable examples of monoterpenes include, but are not limited to,limonene, pinene, cintronellol, terpinene, nerol, menthane, carveol,S-linalool, safrol, cinnamic acid, apiol, geraniol, thymol, citral,carvone, camphor, etc. and derivatives thereof. For information aboutthe structure and synthesis of terpenes, including terpenes of theinvention, see Kirk-Othmer Encyclopedia of Chemical Technology, Mark, etal., eds., 22:709-762 3d Ed (1983), the teachings of which areincorporated herein in their entirety.

In particular, suitable limonene derivatives include perillyl alcohol,perillic acid, cis-dihydroperillic acid, trans-dihydroperillic acid,methyl esters of perillic acid, methyl esters of dihydroperillic acid,limonene-2-diol, uroterpenol, and combinations thereof.

Formulation of one or more of the following: CoQ, ubiquinol, lipoicacid, fatty acid(s) and, optionally, additional components, can beaccomplished by many methods known in the art. For example, theubiquinol, lipoic acid, fatty acid composition can be formulated in asuspension, an emulsion, an elixir, a solution, a caplet that harborsthe liquid, or in a soft gelatin capsule (that harbors the liquid).Often the formulation will include an acceptable carrier, such as oil,or other suspending agent.

Suitable carriers include but are not limited to, for example, fattyacids, esters and salts thereof, that can be derived from any source,including, without limitation, natural or synthetic oils, fats, waxes orcombinations thereof. Moreover, the fatty acids can be derived, withoutlimitation, from non-hydrogenated oils, partially hydrogenated oils,fully hydrogenated oils or combinations thereof. Non-limiting exemplarysources of fatty acids (their esters and salts) include seed oil, fishor marine oil, canola oil, vegetable oil, safflower oil, sunflower oil,nasturtium seed oil, mustard seed oil, olive oil, sesame oil, soybeanoil, corn oil, peanut oil, cottonseed oil, rice bran oil, babassu nutoil, palm oil, low erucic rapeseed oil, palm kernel oil, lupin oil,coconut oil, flaxseed oil, evening primrose oil, jojoba, tallow, beeftallow, butter, chicken fat, lard, dairy butterfat, shea butter orcombinations thereof.

Specific non-limiting exemplary fish or marine oil sources includeshellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy,herring, trout, sardines or combinations thereof. In particular, thesource of the fatty acids is fish or marine oil (DHA or EPA), soybeanoil or flaxseed oil. Alternatively or in combination with one of theabove identified carriers, beeswax can be used as a suitable carrier, aswell as suspending agents such as silica (silicon dioxide).

The formulations of the invention are considered dietary supplementsuseful to the increase the amounts of CoQ and/or optional nutritiveingredients in individuals in need thereof.

Alternatively, the formulations of the invention are also considered tobe nutraceuticals. The term “nutraceutical” is recognized in the art andis intended to describe specific chemical compounds found in foods thatmay prevent disease. CoQ-10 and amino acids are such compounds.

The formulations of the invention can further include variousingredients to help stabilize, or help promote the bioavailability ofthe CoQ and/or amino acid(s), or serve as additional nutrients to anindividual's diet. Suitable additives can include vitamins andbiologically-acceptable minerals. Non-limiting examples of vitaminsinclude vitamin A, B vitamins, vitamin C, vitamin D, vitamin E, vitaminK and folic acid. Non-limiting examples of minerals include iron,calcium, magnesium, potassium, copper, chromium, zinc, molybdenum,iodine, boron, selenium, manganese, derivatives thereof or combinationsthereof. These vitamins and minerals may be from any source orcombination of sources, without limitation. Non-limiting exemplary Bvitamins include, without limitation, thiamine, niacinamide, pyridoxine,riboflavin, cyanocobalamin, biotin, pantothenic acid or combinationsthereof.

Vitamin(s), if present, are present in the composition of the inventionin an amount ranging from about 5 mg to about 500 mg. More particularly,the vitamin(s) is present in an amount ranging from about 10 mg to about400 mg. Even more specifically, the vitamin(s) is present from about 250mg to about 400 mg. Most specifically, the vitamin(s) is present in anamount ranging from about 10 mg to about 50 mg. For example, B vitaminsare in usually incorporated in the range of about 1 milligram to about10 milligrams, i.e., from about 3 micrograms to about 50 micrograms ofB12. Folic acid, for example, is generally incorporated in a range ofabout 50 to about 400 micrograms, biotin is generally incorporated in arange of about 25 to about 700 micrograms and cyanocobalamin isincorporated in a range of about 3 micrograms to about 50 micrograms.

Mineral(s), if present, are present in the composition of the inventionin an amount ranging from about 25 mg to about 1000 mg. Moreparticularly, the mineral(s) are present in the composition ranging fromabout 25 mg to about 500 mg. Even more particularly, the mineral(s) arepresent in the composition in an amount ranging from about 100 mg toabout 600 mg.

Various additives can be incorporated into the present compositions.Optional additives of the present composition include, withoutlimitation, phospholipids, L-carnitine, starches, sugars, fats,antioxidants, amino acids, proteins, flavorings, coloring agents,hydrolyzed starch(es) and derivatives thereof or combinations thereof.

As used herein, the term “phospholipid” is recognized in the art, andrefers to phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidyl choline, phosphatidyl ethanolamine, as well asphosphatidic acids, ceramides, cerebrosides, sphingomyelins andcardiolipins.

As used herein, the term “antioxidant” is recognized in the art andrefers to synthetic or natural substances that prevent or delay theoxidative deterioration of a compound. Exemplary antioxidants includetocopherols, flavonoids, catechins, superoxide dismutase, lecithin,gamma oryzanol; vitamins, such as vitamins A, C (ascorbic acid) and Eand beta-carotene; natural components such as camosol, carnosic acid androsmanol found in rosemary and hawthorn extract, proanthocyanidins suchas those found in grapeseed or pine bark extract, and green tea extract.

The term “flavonoid” as used herein is recognized in the art and isintended to include those plant pigments found in many foods that arethought to help protect the body from cancer. These include, forexample, epi-gallo catechin gallate (EGCG), epi-gallo catechin (EGC) andepi-catechin (EC).

Any dosage forms, and combinations thereof, are contemplated by thepresent invention. Examples of such dosage forms include, withoutlimitation, chewable tablets, elixirs, liquids, solutions, suspensions,emulsions, capsules, soft gelatin capsules, hard gelatin capsules,caplets, lozenges, chewable lozenges, suppositories, creams, topicals,ingestibles, injectables, infusions, health bars, confections, animalfeeds, cereals, cereal coatings, and combinations thereof. Thepreparation of the above dosage forms are well known to persons ofordinary skill in the art.

For example, health bars can be prepared, without limitation, by mixingthe formulation plus excipients (e.g., binders, fillers, flavors,colors, etc.) to a plastic mass consistency. The mass is then eitherextended or molded to form “candy bar” shapes that are then dried orallowed to solidify to form the final product.

Soft gel or soft gelatin capsules can be prepared, for example, withoutlimitation, by dispersing the formulation in an appropriate vehicle(e.g. rice bran oil, monoterpene, fatty acid(s) and/or beeswax orcombinations thereof) to form a high viscosity mixture. This mixture isthen encapsulated with a gelatin based film using technology andmachinery known to those in the soft gel industry. The industrial unitsso formed are then dried to constant weight. Typically, the weight ofthe capsule is between about 100 to about 2500 milligrams and inparticular weigh between about 1500 and about 1900 milligrams, and morespecifically can weigh between about 1500 and about 2000 milligrams.

For example, when preparing soft gelatin shells, the shell can includebetween about 20 to 70 percent gelatin, generally a plasticizer andabout 5 to about 60% by weight sorbitol. The filling of the soft gelatincapsule is liquid (principally limonene, in combination with rice branoil and/or beeswax if desired) and can include, apart form theantioxidant actives, a hydrophilic matrix. The hydrophilic matrix, ifpresent, is a polyethylene glycol having an average molecular weight offrom about 200 to 1000. Further ingredients are optionally thickeningagents. In one embodiment, the hydrophilic matrix includes polyethyleneglycol having an average molecular weight of from about 200 to 1000, 5to 15% glycerol, and 5 to 15% by weight of water. The polyethyleneglycol can also be mixed with propylene glycol and/or propylenecarbonate.

In another embodiment, the soft gel capsule is prepared from gelatin,glycerine, water and various additives. Typically, the percentage (byweight) of the gelatin is between about 30 and about 50 weight percent,in particular between about 35 and about weight percent and morespecifically about 42 weight percent. The formulation includes betweenabout 15 and about 25 weight percent glycerine, more particularlybetween about 17 and about 23 weight percent and more specifically about20 weight percent glycerine.

The remaining portion of the capsule is typically water. The amountvaries from between about 25 weigh percent and about 40 weight percent,more particularly between about 30 and about 35 weight percent, and morespecifically about 35 weight percent. The remainder of the capsule canvary, generally, between about 2 and about 10 weight percent composed ofa flavoring agent(s), sugar, coloring agent(s), etc. or combinationthereof. After the capsule is processed, the water content of the finalcapsule is often between about 5 and about 10 weight percent, moreparticularly 7 and about 12 weight percent, and more specificallybetween about 9 and about 10 weight percent.

As for the manufacturing, it is contemplated that standard soft shellgelatin capsule manufacturing techniques can be used to prepare thesoft-shell product. Examples of useful manufacturing techniques are theplate process, the rotary die process pioneered by R. P. Scherer, theprocess using the Norton capsule machine, and the Accogel machine andprocess developed by Lederle. Each of these processes is maturetechnologies and are all widely available to any one wishing to preparesoft gelatin capsules.

Typically, when a soft gel capsule is prepared, the total weight isbetween about 250 milligrams and about 2.5 gram in weight, e.g., 400-750milligrams. Therefore, the total weight of additives, such as vitaminsand antioxidants, is between about 80 milligrams and about 2000milligrams, alternatively, between about 100 milligrams and about 1500milligrams, and in particular between about 120 milligrams and about1200 milligrams. In particular, the soft gel capsule typically weighsbetween about 1000 milligrams and 1300 milligrams, wherein thepercentage fill is about 50% of the entire weight of the capsule, i.e.,from about 500 to about 650 milligrams fill weight. The fill weightincludes the active ingredient(s), solubilizing agents, etc.

Preparation of the soft gel capsules was accomplished by methods wellknown in the art including, but not limited to those describedthroughout the specification and in U.S. Pat. Nos. 6,616,942, 6,623,734and pending U.S. Ser. Nos. 10/035,753 and 09/825,920, the contents ofwhich are incorporated herein by reference in their entirety.

For example, a soft gel capsule can be prepared by mixing alpha lipoicacid with ubiquinol and/or CoQ-10 with one or more fatty acids untildissolution occurs. To the solution can then be added a carrier, such asa monoterpene, e.g., limonene. The solution is then encapsulated withina gelatin capsule as described above.

The present invention also provides packaged formulations andinstructions for use of the tablet, capsule, elixir, etc. Typically, thepackaged formulation, in whatever form, is administered to an individualin need thereof that requires an increase in the amount of reduced oroxidized CoQ in the individual's diet. Typically, the dosage requirementis between about 1 to about 4 dosages a day.

CoQ-10 has been implicated in various biochemical pathways and issuitable for the treatment of cardiovascular conditions, such as thoseassociated with, for example, statin drugs that effect the body'sability to product CoQ-10 naturally. CoQ-10 has also been implicated invarious periodontal diseases. Furthermore, CoQ-10 has been implicated inmitochondrial related diseases and disorders, such as the inability toproduce acetyl coenzyme A, neurological disorders, for example, such asParkinson's disease and, Prater-Willey syndrome.

The following paragraphs enumerated consecutively from 1 through 33provide for various aspects of the present invention. In one embodiment,in a first paragraph (1), the present invention provides a soft gelatincapsule, comprising an encapsulated solution comprising a ubiquinol; asufficient quantity of lipoic acid to maintain the ubiquinol in itsreduced form; and one or more fatty acids, such that the ubiquinolcomprises about 95% by weight of a total amount of ubiquinol andcoenzyme Q in the solution.

2. The soft gelatin capsule of paragraph 1, wherein the ubiquinolcontent is about 98% by weight of the total weight of ubiquinol andcoenzyme Q in the solution.

3. The soft gelatin capsule of paragraph 2, wherein the ubiquinolcontent is about 99% by weight of the total weight of ubiquinol andcoenzyme Q in the solution.

4. The soft gelatin capsule of any of paragraphs 1 through 3, whereinthe molar ratio of lipoic acid to ubiquinol is from about 0.1:1 to about2.5:1.

5. The soft gelatin capsule of any of paragraphs 1 through 4, whereinthe fatty acid is butanoic acid, hexanoic acid, octanoic acid, decanoicacid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid,9-hexadecenoic acid, octadecanoic acid, 9-octadecenoic acid,12-hydroxy-9-octadecenoic acid, 11-octadecenoic acid,9,12-octadecadienoic acid, 9,12,15-octadecatrienoic acid,6,9,12-octadecatrienoic acid, eicosanoic acid, 9-eicosenoic acid,5,8,11,14-eicosatetraenoic acid, 5,8,11,14,17-eicosapentaenoic acid,docosanoic acid, 13-docosenoic acid, 4,7,10,13,16,19-docosahexaenoic,tetracosanoic acid or mixtures thereof.

6. The soft gelatin capsule of paragraph 5, wherein the fatty acid is acombination of decanoic acid and octanoic acid.

7. The soft gelatin capsule of paragraph 6, wherein the ratio ofdecanoic acid to octanoic acid is 3:7.

8. The soft gelatin capsule of any of paragraphs 1 through 7, furthercomprising a monoterpene.

9. The soft gelatin capsule of paragraph 8, wherein the monoterpene islimonene or a derivative thereof.

10. The soft gelatin capsule of paragraph 9, wherein the limonenederivative is perillyl alcohol, perillic acid, cis-dihydroperillic acid,trans-dihydroperillic acid, methyl esters of perillic acid, methylesters of dihydroperillic acid, limonene-2-diol, uroterpenol, or acombination thereof.

11. The soft gelatin capsule of any of paragraphs 1 through 10, whereinthe encapsulated ubiquinol solution is stable to oxidation for at leastabout 30 days, such that about 95% ubiquinol remains from the originaltotal amount of ubiquinol and coenzyme Q in the solution.

12. The soft gelatin capsule of any of paragraphs 1 through 11, whereinthe encapsulated ubiquinol solution is stable to oxidation for at leastabout 120 days, such that about 95% ubiquinol remains from the originaltotal amount of ubiquinol and coenzyme Q in the solution.

13. The soft gelatin capsule of any of paragraphs 1 through 12, whereinthe encapsulated ubiquinol solution is stable to oxidation for at leastabout 365 days, such that about 95% ubiquinol remains from the originaltotal amount of ubiquinol and coenzyme Q in the solution.

14. A method for the delivery of an effective amount of ubiquinol to anindividual in need thereof, comprising the steps of

providing a soft gelatin capsule as in paragraph 1, such that aneffective amount of ubiquinol is provided to an individual.

15. A packaged nutraceutical formulation comprising:

a soft gelatin capsule as in paragraph 1 and

instructions for use thereof.

16. A method to prevent oxidation of a ubiquinol to a ubiquinone or asemi-ubiquinone, comprising the step of:

contacting a sufficient amount of alpha lipoic acid with ubiquinol, suchthat oxidation of the ubiquinol to a ubiquinone or a semi-ubiquinonedoes not occur.

17. A soft gelatin capsule, comprising an encapsulated solutioncomprising:

a ubiquinol;

a sufficient quantity of lipoic acid to maintain the ubiquinol in itsreduced form; and

a monoterpene, such that the ubiquinol comprises about 95% by weight ofa total amount of ubiquinol and coenzyme Q in the solution.

18. The soft gelatin capsule of paragraph 17, wherein the ubiquinolcontent is about 98% by weight of the total weight of ubiquinol andcoenzyme Q in the solution.

19. The soft gelatin capsule of paragraph 18, wherein the ubiquinolcontent is about 99% by weight of the total weight of ubiquinol andcoenzyme Q in the solution.

20. The soft gelatin capsule of paragraph 17, wherein the ratio oflipoic acid to ubiquinol is from about 0.1:1 to about 2.5:1.

21. The soft gelatin capsule of paragraph 17, wherein the monoterpene islimonene or a derivative thereof.

22. The soft gelatin capsule of paragraph 21, wherein the limonenederivative is perillyl alcohol, perillic acid, cis-dihydroperillic acid,trans-dihydroperillic acid, methyl esters of perillic acid, methylesters of dihydroperillic acid, limonene-2-diol, uroterpenol, or acombination thereof.

23. The soft gelatin capsule of paragraph 17, wherein the encapsulatedubiquinol solution is stable to oxidation for at least about 30 days,such that about 95% ubiquinol remains from the original total amount ofubiquinol and coenzyme Q in the solution.

24. The soft gelatin capsule of paragraph 17, wherein the encapsulatedubiquinol solution is stable to oxidation for at least about 120 days,such that about 95% ubiquinol remains from the original total amount ofubiquinol and coenzyme Q in the solution.

25. The soft gelatin capsule of paragraph 17, wherein the encapsulatedubiquinol solution is stable to oxidation for at least about 365 days,such that about 95% ubiquinol remains from the original total amount ofubiquinol and coenzyme Q in the solution.

26. A method for the delivery of an effective amount of ubiquinol to anindividual in need thereof, comprising the steps of

providing a soft gelatin capsule as in paragraph 17, such that aneffective amount of ubiquinol is provided to an individual.

27. A packaged nutraceutical formulation comprising:

a soft gelatin capsule as in paragraph 1 and

instructions for use thereof.

28. The method of paragraph 16, wherein the percentage of the ubiquinolto the oxidized ubiquinone or the semi-ubiquinone on a weight basis isat least 95%.

29. The method of paragraph 16, wherein the percentage of the ubiquinolto oxidized ubiquinone or the semi-ubiquinone on a weight basis is atleast 98%.

30. The method of any of paragraphs 16, 28 or 29, wherein the ubiquinolremains reduced for at least about 30 days.

31. The method of any of paragraphs 16, 28 or 29, wherein the ubiquinolremains reduced for at least about 120 days.

32. The method of any of paragraphs 16, 28 or 29, wherein the ubiquinolremains reduced for at least about 365 days.

33. The method of any of paragraphs 16 or 28 through 32, wherein themolar ratio of lipoic acid to ubiquinol is from about 0.1:1 to about2.5:1.

The invention will be further described with reference to the followingnon-limiting Examples. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described withoutdeparting from the scope of the present invention. Thus the scope of thepresent invention should not be limited to the embodiments described inthis application, but only by embodiments described by the language ofthe claims and the equivalents of those embodiments. Unless otherwiseindicated, all percentages are by weight.

EXAMPLES

Ubiquinol (QH™, Kaneka Corporation, Functional Foods DevelopmentDivision, 3-2; 1-, Nakanoshima, Kita-Ku, Osaka 530-8288, Japan)formulation trial #1:

QH™ working solution (ws): 20.0 g QH™ was mixed in 60.0 g D-Limonene(LI-FA-MX-00454) at ˜30° C. until completely dissolved. The beaker wasnitrogen-blanketed and put aside for mixing the trial formulations.

Alpha-Lipoic Acid (ALA) working solution (ws): A 25%(w/w)(weight/weight) ALA solution was prepared with 7:3 caprylic acid:capric acid at ˜30° C. until completely dissolved.

The following trial mixes were prepared:

Trial mix #1 (100 mg QH™/400 mg): 8.0 g of the QH™ working solution wereplaced into a small glass vial, nitrogen blanketed and labeled: 100 mgQH™/400 mg.

Trial mix #2 (100 mg QH™/425 mg): 7.53 g of the QH™ ws and 0.47 g of theALA ws were mixed, placed into a small vial, nitrogen blanketed andlabeled: 100 mg QH™/425 mg.

Trial mix #3 (100 mg QH™/450 mg): 7.11 g QH™ ws and 0.89 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/450 mg.

Trial mix #4 (100 mg QH™/500 mg): 6.40 g QH™ ws and 1.60 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/500 mg.

trial mix #5 (100 mg QH™/650 mg): 4.92 g QH™ ws and 3.08 g ALA ws weremixed, placed in a small vial, nitrogen blanketed and labeled: 100 mgQH™/650 mg.

Trial mix #6 (100 mg QH™/900 mg): 3.56 g QH™ ws and 4.44 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/900 mg.

Trial mix #7 (100 mg QH™/1000 mg): 3.20 g QH™ ws and 4.80 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/1000 mg.

Trial mix #8 (100 mg QH™/1250 mg): 2.56 g QH™ ws and 5.44 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/1250 mg.

Trial mix #9 (100 mg QH™/1500 mg): 2.13 g QH™ ws and 5.87 g ALA ws weremixed, placed into a small vial, nitrogen blanketed and labeled: 100 mgQH™/1500 mg.

The remainder of QH™ working solution was placed into large amber glassvials, nitrogen blanketed and labeled: QH™ working solution 25%, datedand place into refrigerator.

100 in the trials represents 100 mg ubiquinol/CoQ10 per dosage formula,and the denominator is for the total fill weight for each dosage. Eachformulation is for 100 mg/ubiquinol/CoQ10 per dosage. A standard amountof ubiquinol/CoQ10 was maintained, adding increasing amounts of ALAsolution, to determine an optimal amount/range for reduction ofoxidation. To keep the potencies at 100 mg/dosage, the fill weights wereincreased as the ALA was increased; hence the 100 mg CoQ10/increasingformula fill weights.

The vials were stored at ambient temperature. Samples were removed overtime and analyzed for ubiquinol and for CoQ10 (oxidized form) via HPLC.Knowing how much ubiquinol/CoQ10 was present in each sample, adetermination was made regarding the amount of CoQ10 or ubiquinolassayed from the total and a determination regarding oxidation was made.The table below shows the amount of ubiquinol remaining after 36 days atroom temperature.

Fill Weight moles moles QH:ALA % QH remaining Sample #: (mg): QH: ALA:(moles) after 36 days 1 400 0.26 0 0 65 2 425 0.26 0.0303 1:0.117 100 3450 0.26 0.0606 1:0.233 93 4 500 0.26 0.1212 1:0.466 95 5 650 0.260.3032 1:1.660 96 6 900 0.26 0.6052 1:2.328 93 7 1000 0.26 0.72701:2.796 Not reliable 8 1250 0.26 1.2218 1:4.699 Not reliable 9 1500 0.261.333 1:5.128 Not reliable variance of amount of % QH remaining ± 2%

Soft gelatin capsules encapsulating ubiquinol/CoQ10 or mixtures thereofwith a fatty acid mixture and alpha-lipoic acid can be prepared by thefollowing general procedure. Caprylic acid and capric acid are pouredinto a blending machine and stirred until clear and completely liquid.The liquid can then be heated and alpha lipoic acid is added and mixeduntil completely dissolved. This solution is the set aside.

D-limonene is added to a blending machine and gently warmed to about 30°C.

Ubiquinol (or CoQ-10 or mixtures thereof) is added to D-limonene andstirred. Optionally, the ubiquinol is added directly to the liquid fattyacid/alpha lipoic acid solution without the use of D-limonene.

The alpha lipoic acid/capric acid/caprylic acid solution is added to theubiquinol/D-limonene solution and mixed. Optionally, the ubiquinol isadded directly to the liquid fatty acid/alpha lipoic acid solutionwithout the use of D-limonene.

The solution is then filtered and encapsulated in soft gelatin capsules.

Exemplary Soft Gel Formulations

The following are general processes used to prepare soft gelatincapsules containing varying amounts of ubiquinol.

15.02 g of capric acid and 35.04 of caprylic acid (3:7) were mixed with299.95 g D-limonene in a blending machine, under vacuum, at atemperature between about 23-30° C. until uniformly mixed and in aliquid state.

12.52 g alpha lipoic acid and 99.98 g ubiquinol (QH™) were added to thewarmed mixture and mixed under vacuum at a temperature between about23-30° C. until completely dissolved.

The resultant liquid mixture was encapsulated into a soft gelatincapsule using the procedures described above. The fill weight for eachcapsule was approximately 465 mg, giving a little over 100 mg ubiquinolper capsule.

Specific Formulations:

Caprylic acid and capric acid were poured into a blending machine andstirred until clear and completely liquid. The solution was heated toabout 30° C. and alpha lipoic acid was added and stirred untilcompletely dissolved. This solution was set aside until needed.

A blending machine was nitrogen blanketed, D-limonene was poured into itand heated to about 30° C. Ubiquinol was added to the D-limonene andstirred under vacuum for at least 20 minutes. The alpha lipoicacid/capric acid/caprylic acid was added to the ubiquinol/D-limonenesolution, heated to about 30° C., then mixed under vacuum for at least40 minutes.

The solution was then filtered, placed into a nitrogen blanketedreceiver and sent for encapsulation.

CoQH-CF 50 mg:

Ubiquinol (QH- Kaneka) 53.1250 mg (98% material so an overage is used tomake 50 mg) Capric acid 4.6850 mg D-limonene 95% 168.1250 mg Alphalipoic acid 3.1250 mg Caprylic acid 10.9400 mg Total capsule fill weight240.0000 mg

CoQH-CF 100 mg:

Ubiquinol (QH- Kaneka) 106.2500 mg (98% material so an overage is usedto make 100 mg) Capric acid 9.3700 mg D-limonene 336.2500 mg Alphalipoic acid 6.2500 mg Caprylic acid 21.8800 mg Total capsule fill weight480.0000 mg

CoQH-CF 100 Mg (with Stability Testing Performed on EncapsulatedSolution:

Ubiquinol (QH-Keneka) 104.13 mg Alpha-lipoic acid 6.25 mg Capric acid9.37 mg Caprylic acid 21.88 mg D-Limonene 336.25 mg Total capsule fillweight 480.00 mg

Measurement at room temperature via HPLC Time zero 3 months 6 monthsUbiquinol 100-104%* 104% 102% *percentage over 100% as an overage ofubiquinol was used variance of amount of % QH remaining ± 2%

Samples were encapsulated in soft gelatin capsules as described aboveand stored at ambient temperature. Capsules were then sampled by openingthe capsule and removing the solution for testing by HPLC.

Although the present invention has been described with reference topreferred embodiments, persons skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

All literature and patent references cited throughout the applicationare incorporated by reference into the application for all purposes.

What is claimed is:
 1. A method of reducing oxidation of an ubiquinol toa ubiquinone or a semi-ubiquinone, comprising the step of: contacting asufficient amount of alpha lipoic acid with ubiquinol to form asolution; wherein a molar ratio of alpha lipoic acid to ubiquinol isfrom 0.1:1 to 0.4:1; and, thus reducing oxidation of the ubiquinol to aubiquinone or a semi-ubiquinone.
 2. The method of claim 1, wherein theubiquinol content of the solution is about 95% by weight of the totalweight of ubiquinol, ubiquinone, and semi-ubiquinone in the solution. 3.The method of claim 1, wherein the solution further comprises a fattyacid selected from the group consisting of butanoic acid, hexanoic acid,octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, 9-hexadecenoic acid, octadecanoic acid,9-octadecenoic acid, 12-hydroxy-9-octadecenoic acid, 11-octadecenoicacid, 9,12-octadecadienoic acid, 9,12,15-octadecatrienoic acid,6,9,12-octadecatrienoic acid, eicosanoic acid, 9-eicosenoic acid,5,8,11,14-eicosatetraenoic acid, 5,8,11,14,17-eicosapentaenoic acid,docosanoic acid, 13-docosenoic acid, 4,7,10,13,16,19-docosahexaenoic,tetracosanoic acid or mixtures thereof.
 4. The method of claim 3,wherein the fatty acid is a combination of decanoic acid and octanoicacid.
 5. The method of claim 4, wherein decanoic acid to octanoic acidis present in a ratio of 3:7.
 6. The method of claim 1, wherein thesolution further comprises a monoterpene.
 7. The method of claim 6,wherein the monoterpene is limonene or a derivative thereof.
 8. Themethod of claim 7, wherein the limonene is d-limonene.
 9. The method ofclaim 1, wherein the ubiquinol in the solution is stable to oxidationfor about 30 days, such that about 95% ubiquinol remains from theoriginal total amount of ubiquinol.
 10. The method of claim 1, whereinthe ubiquinol in the solution is stable to oxidation for about 120 days,such that about 95% ubiquinol remains from the original total amount ofubiquinol.
 11. The method of claim 1, wherein the ubiquinol in thesolution is stable to oxidation for about 365 days, such that about 95%ubiquinol remains from the original ubiquinol.
 12. The method of claim1, further comprising the step of: encapsulating the solution containingalpha lipoic acid and ubiquinol in a soft gelatin capsule.
 13. Themethod of claim 12, further comprising the steps of: administering oneor more soft gelatin capsules to an individual, such that an effectiveamount of ubiquinol is provided to the individual.
 14. The method ofclaim 2, wherein the ubiquinol content is about 98% by weight of thetotal weight of ubiquinol, ubiquinone, and semi-ubiquinone in thesolution.
 15. The method of claim 14, wherein the ubiquinol content isabout 99% by weight of the total weight of ubiquinol, ubiquinone, andsemi-ubiquinone in the solution.
 16. The method of claim 1, furthercomprising a fatty acid and a monoterpene.
 17. The method of claim 16,wherein the fatty acid is decanoic acid, octanoic acid, or a combinationthereof, and the monoterpene is limonene or a derivative thereof. 18.The method of claim 17, wherein the fatty acid is a combination ofdecanoic acid and octanoic acid, and the limonene is d-limonene.